Every cytotoxic agent used in the treatment of cancer causes damage to normal as well as malignant cells. The maximum therapeutically useful dose is limited by toxicity to essential normal tissues, and in many cases it is not possible to give a dose large enough to destroy the cancer without also killing the patient. However, if the concentration of the cytotoxic drug could be increased in the malignant tissues only, then the therapeutic effectiveness of the drug would be increased without a corresponding increase in toxicity.
Certain types of tissue abnormalities, disease processes, and infections are characterized by abnormally high levels of activity of specific extracellular and/or intracellular proteases. To date, at least 144 different types of proteases had been identified in mammalian cells. Other types of protease are produced by various pathogenic bacteria, fungi, protozoa, or parasites. It has become clear that proteases play a key regulatory role in a great variety of intracellular and extracellular processes. In addition to their well-known digestive functions in the stomach and intestine, proteases are involved in the coagulation process, complement activation, fertilization, tissue remodelling during growth and development, the activation of other enzymes, and the formation and release of a wide variety of peptide hormones.
As might be expected in view of their important role in the regulation of mammalian cell functions, the activity of certain intracellular and extracellular proteases can be altered by disease processes that involve tissue injury, necrosis, inflammation, repair, or degeneration. Abnormally high activities of certain specific proteases are present at the sites of physical or chemical trauma, blood clots, malignant tumors, rheumatoid arthritis, inflammatory bowel disease, gingival disease, glomerulonephritis, and acute pancreatitis. Abnormal protease activity occurs in disseminated intravascular coagulation, and is suspected to be involved in the development of liver fibrosis, pulmonary emphysema, atherosclerosis, and muscular dystrophy. Consequently, attempts have been made (with some success) in both patients and experimental animals to retard the progression of some of these diseases by the administration of appropriate protease inhibitors.
Various pathogenic bacteria, fungi, and protozoa secrete unique proteases. Consequently, localized infections may be associated with a localized concentration of specific protease activity. Cells involved in the reaction of the host cells against such infections also secrete proteases.
Thus, there is need for a therapy that is designed to make use of the abnormally high levels of activity of specific types of extracellular proteases that characterize certain tissue abnormalities, disease processes, and infections. In summary, instead of attempting to block the activity of such proteases, use is made of their activity to induce a preferential accumulation of selected therapeutic and/or diagnostic compounds at the extracellular site of the abnormal activity.
Increasing the cellular or tissue specificity of a therapeutic or diagnostic agent will improve its therapeutic ratio and/or the sensitivity of detection or visualization of certain types of lesions. Although localized disease processes may lead to a wide range of systemic abnormalities, usually the primary goal of treatment is to bring the localized disease under control. Under most conditions the therapeutic effectiveness of a given agent is directly related to its concentration in the diseased cells or tissues, while its systemic toxicity is related to its concentration in various susceptible cells and tissues in other parts of the body. Consequently, it may be predicted that the maximum safe dose (and therefore the therapeutic effectiveness) of a given agent will increase without a corresponding increase in systemic toxicity if that agent can be made more specific for its target cells or tissues. An increase in specificity is of particular value for agents whose therapeutic effectiveness is limited at present by serious systemic toxicity.
Certain radiolabelled or fluorescent compounds such as dihematoporphyrin ether that show a useful degree of specificity for certain types of cellular or tissue abnormalities are used clinically at present to detect and/or visualize those abnormalities. Any significant improvement in the specificity of such compounds for the lesions in question will improve the sensitivity of the technique.